CHAPTER 2-40: CARBAMAZEPINE AND OXCARBAZEPINE

INTRODUCTION

Carbamazepine (Tegretol), an iminostilbene compound, was introduced in the United States in 1974 for the treatment of trigeminal neuralgia. It has become a first-line drug for the treatment of generalized and partial complex seizure disorders and has found expanded use for pain syndromes, psychiatric illnesses, and drug withdrawal reactions. Oxcarbazepine (Trileptal) was approved by the US FDA in 2000 and is the 10-keto analog of carbamazepine. It is considered a prodrug with a principal metabolite, 10,11-dihydro-10-hydroxycarbazepine (monohydroxy derivative [MHD]) that is responsible for its principal therapeutic and toxic effects, which are similar to those of carbamazepine.

MECHANISM OF TOXICITY

1. Carbamazepine. Most toxic manifestations appear to be related to its CNS-depressant and anticholinergic effects. It also alters cerebellar-vestibular brainstem function. In addition, presumably because its chemical structure is similar to that of the tricyclic antidepressant imipramine, acute carbamazepine overdose can cause seizures and cardiac conduction disturbances.

2. Oxcarbazepine is a CNS depressant and seems to lack the toxicity profile of carbamazepine. This may be attributed to the limited rate of production of the active metabolite and lack of a toxic epoxide metabolite. The exception may be a dose-related nephrogenic dilutional hyponatremia.

3. Pharmacokinetics (see also Table II–66)

   1. Carbamazepine is slowly and erratically absorbed from the GI tract, and peak levels may be delayed for 6–24 hours, particularly after an overdose (continued absorption for over 100 hours has been reported with extended-release preparations). The exception may be with oral suspension dosage forms, whose absorption may be rapid, with symptoms occurring within 30 minutes of ingestion. It is 75–78% protein bound with a volume of distribution of approximately 1.4 L/kg (up to 3 L/kg after overdose). Up to 28% of a dose is eliminated in the feces, and there is enterohepatic recycling. The parent drug is metabolized by cytochrome P450, and 40% is converted to its 10,11-epoxide, which is as active as the parent compound. The elimination half-life is variable and subject to autoinduction of cytochrome P450 enzymes; the half-life of carbamazepine is approximately 18–55 hours (initially) to 5–26 hours (with long-term use). The half-life of the epoxide metabolite is approximately 5–10 hours.

   2. Oxcarbazepine is well absorbed from the GI tract (bioavailability >95%) and metabolized rapidly (half-life of 1–5 hours) to its active metabolite, MHD, with peak levels achieved at 1–3 hours and 4–12 hours for the parent and the active metabolite, respectively. The active metabolite has 30–40% protein binding, a volume of distribution of 0.8 L/kg, and a half-life of 7–20 hours (average, 9 hours). The active metabolite is not subject to autoinduction.

TOXIC DOSE

1. Carbamazepine. Acute ingestion of more than 10 mg/kg can result in a blood level above the therapeutic range of 4–12 mg/L. The recommended maximum daily dose is 1.6–2.4 g in adults (35 mg/kg/d in children). Death has occurred after adult ingestion of 3.2–60 g, but survival has been reported after an 80-g ingestion. ...